The present invention relates generally to separation of compounds and, particularly, to separation of compounds based upon differences in the fluorous nature of the compounds.
References set forth herein may facilitate understanding of the present invention or the background of the present invention. Inclusion of a reference herein, however, is not intended to and does not constitute an admission that the reference is available as prior art with respect to the present invention.
The separation of fluorous compounds from non-fluorous, organic compounds and/or from other fluorous compounds having a different fluorous nature is increasingly popular. Various fluorous separation techniques or methods are used to separate mixtures containing, for example, organic molecules and one or more fluorous molecules (organic molecules bearing fluorous domains or tags) from each other based predominantly on the fluorous nature of molecules (for example, the absence of a fluorous domain, the size of a fluorous domain and/or structure of a fluorous domain or molecule). In general, differences in the fluorous nature of molecules affect the interaction of the molecules with a “fluorophilic” or fluorous phase in the fluorous separation method. Early fluorous separation methods based on liquid-liquid separations have been augmented by solid-liquid separations like fluorous solid phase extraction (FSPE) and fluorous chromatography. See, for example, Zhang, W. Tetrahedron 2003, 59, 4475-4489; Curran, D. P. In Stimulating Concepts in Chemistry; Vögtle, F., Stoddardt, J. F., Shibasaki, M., Eds.; Wiley-VCH: New York, 2000; Dobbs, A. P.; Kimberley, M. R. J. Fluorine Chem. 2002, 118, 3-17; Barthel-Rosa, L. P.; Gladysz, J. A. Coord. Chem. Rev. 1999, 192, 587-605; Curran, D. P. Synlett 2001, 1488-1496; and U.S. Pat. Nos. 6,734,318, 6,727,390. 6,156,896, 5,859,247, and 5,777,121. Most of these types of separations rely on a fluorous silica solid phase (silica gel with a fluorocarbon bonded phase) coupled with an organic solvent.
Since their introduction in 1997, standard fluorous solid phase extractions have proven broadly useful for separating light fluorous molecules from organic molecules. See, for example, Curran, D. P.; Hadida, S.; He, M. J. Org. Chem. 1997, 62, 6714-6715; Zhang, Q.; Luo, Z.; Curran, D. P. J. Org. Chem. 2000, 65, 8866-8873. As illustrated in FIG. 1A, in a standard fluorous solid phase extraction to separate organic and fluorous compounds, a mixture of organic and fluorous compounds is loaded onto a “fluorophilic” (fluorous) silica gel followed by first pass elution with a “fluorophobic” (non-fluorous) solvent. Polar organic solvents (for example, 80-100% aqueous methanol or acetonitrile) are the most common fluorophobic solvents. During this first elution, the non-tagged organic compound is rapidly washed from the column while the fluorous-tagged compound is retained. A second pass elution (not shown) with a “fluorophilic” solvent (often Et2O or THF) then washes the fluorous fraction from the column.
Fluorous solvents or fluorous eluting fluids also have been used in connection with non-fluorous stationary phases in chromatographic separations of organic, non-fluorous compounds. See, for example, U.S. Pat. Nos. 5,824,225 and 5,968,368, J. A. Attaway, Journal of Chromatography 1967, 31, 231-3; M. Z. Kagan, Journal of Chromatography, A 2001, 918, 293-302; and J. A. Blackwell, L. E. Schallinger, Journal of Microcolumn Separations 1994, 6, 551-6. U.S. Pat. No. 5,824,225 indicates, for example, that use of using low boiling point (hydro)fluorocarbons and (hydro)fluorocarbon ethers as eluting fluids can facilitate removal of such solvents from the compounds which they elute.
Fluorinated eluting fluids have also been used to separate highly fluorinated macromolecules including hydroxyl end groups in silica gel columns. In that regard, European Patent Nos. 538827 and 538828 disclose the chromatographic separation of macromolecular mixtures of perfluoro polyoxyalkylenes in columns containing a stationary phase bearing polar groups able to bond with the hydroxyl end groups of the polymers (for example, a silica gel) using nonpolar fluorinated solvents (for example, 1,1,2,-trichloro-1,2,2-trifluoroethane) as elution agents.
Matsuzawa and Mikami have shown that cyclodextrins form inclusion complexes with fluorous compounds and separated a fluorinated ester (C6H5CO2CH2Rf) tagged with different perfluoroalkyl tags Rf (that is, —CF3, —C2F5, —C3F7, —C7F15 or —C9F19) using HPLC columns packed with β- or γ-cyclodextrins. H. Matsuzawa, K. Mikami, Synlett 2002, 1607-12. In general, the separation tagged compounds synthesized by tagging a single organic compound with tags of differing nature can be effected by many separation techniques and is of little interest. The inclusion complexes formed between cyclodextrins and fluorous compound may result in an HPLC column packed with cyclodextrins bound to silica gel operating similarly to a column packed with fluorous silica gel as the cyclodextrins complex with fluorous solvents used in a separation.
Given the increasing utility and popularity of separations of a wide variety of mixtures of organic compounds based upon differences in fluorous nature, it is desirable to develop additional fluorous separation methods through which different organic compounds can be separated based upon differences in a fluorous nature thereof.